The corticospinal and reticulospinal systems must cooperate for control of reaching and other voluntary movements, but little is known about how this can occur. The studies proposed in this project will use a combined approach of neurophysiology in the awake, behaving monkey and modern neuroanatomical tracing studies to expand knowledge of mechanisms and functions of combined corticospinal and reticulospinal control of upper limb movements. Three cortical motor areas are the subject of the study, the primary motor cortex (M1), the supplementary motor area (SMA), and the dorsal premotor cortex (PMd). M1 and SMA are strong sources of corticospinal projections. PMd is also a source of corticospinal projections, and its activity is well related to whole-arm reaching movements. SMA and PMd are strong sources of corticoreticular projections to the reticulospinal system. The reticulospinal system is studied in the pontomedullary reticular formation (PMRF) of the brainstem. In Aim 1, electrical stimulation of cortical motor areas and the PMRF alone and in concert reveals how outputs from these descending systems combine for control of the ipsilateral and contralateral arm. There is also evidence that the corticospinal system can compete to block output of the reticulospinal system, and this study will reveal how and where that cortical gating of PMRF output occurs. Even at the single neuron level, this project has produced evidence of interactions between corticospinal and reticulospinal neurons, and defining how this relates to control of reaching is the final part of Aim 1. Throughout studies for Aim 1, the subject reaches with both arms, but uses only one arm at a time. Aim 2 employs a different apparatus to require coordinated bimanual exertions. Here, the hypothesis is that reticulospinal neurons will have activity patterns that best match the most common result of electrical stimulation in the PMRF, a double reciprocal pattern between the limbs with ipsilateral flexion and contralateral extension. Additional electrical stimulation studies for Aim 2 will also determine how cortical gating of PMRF output differs when the pattern of bilateral arm exertions matches or departs from the movements produced by the typical PMRF output synergies. Aim 3 employs complementary neuroanatomical studies to define the corticoreticular systems from M1, SMA, and PMd. These studies compare ipsilateral and contralateral sources of corticoreticular projections onto identified reticulospinal neurons. A dual retrograde tracing study from the cervical spinal cord will also show where reticulospinal neurons originate with ipsilateral, contralateral, and bilateral projections to the spinal cord. This line of investigation is of particular relevance for understanding mechanisms of recovery from stroke because contralesional corticoreticular projections have relatively direct access to the impaired limb. Understanding how these systems operate in the normal subject is a pre-requisite to future studies that can clearly define whether this is system is an important alternative pathway for recovery of upper limb function after stroke. No other US laboratory is engaged in studies of this sort in the monkey. PUBLIC HEALTH RELEVANCE: When people have a stroke, the part of the brain usually injured is the cerebral cortex, just under the skull. This usually impairs control of movement on one side of the body. This project studies how the cerebral cortex cooperates with a deep structure called the reticular formation that can also control movement, but is rarely affected by stroke. There is a long held theory that the reticular formation helps take over after stroke, but this has never been directly studied. This project will define how the cortex and reticular formation normally cooperate as a preliminary step to future studies where the potential for these systems to cooperate after stroke can be studied and expanded to improve recovery.